Chemokine-Containing Exosomes Are Released from Heat-Stressed Tumor Cells via Lipid Raft-Dependent Pathway and Act as Efficient Tumor Vaccine (Publication with Expression of Concern. See vol. 211, pg. 1250, 2023)
Chemokine-Containing Exosomes Are Released from Heat-Stressed Tumor Cells via Lipid Raft-Dependent Pathway and Act as Efficient Tumor Vaccine (Publication with Expression of Concern. See vol. 211, pg. 1250, 2023)
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含有趋化因子的外泌体通过脂筏依赖性途径从热应激肿瘤细胞中释放，并作为有效的肿瘤疫苗
DOI：
10.4049/jimmunol.1002991
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发表时间：
2011-02-15
影响因子：
4.4
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Chen, Taoyong;Guo, Jun;Cao, Xuetao
来源于树突状细胞或肿瘤细胞的外泌体是一种纳米大小的膜囊泡，可以诱导特异性抗肿瘤免疫。在研究热疗对抗肿瘤免疫反应的影响时，我们发现热应激肿瘤细胞（HS-TEX）衍生的外泌体比传统肿瘤衍生的外泌体更能化学吸引和激活树突状细胞（DC）和T细胞。我们发现HS-TEX含有趋化因子，如CCL2， CCL3, CCL4， CCL5和CCL20，并且含有趋化因子的HS-TEX在体外和体内都具有化学吸引CD11c+ DC和CD4+/CD8+ T细胞的功能。此外，含有趋化因子的HS-TEX的产生可以被ATP抑制剂、钙螯合剂和胆固醇清除剂抑制，这表明趋化因子进入外泌体的动员是ATP和钙依赖的，并且是通过脂质筏依赖的途径。我们一致发现，热应激后细胞内趋化因子可以在脂筏中富集。因此，瘤内注射HS-TEX比肿瘤源性外泌体更能诱导特异性抗肿瘤免疫应答，从而更显著地抑制肿瘤生长，延长荷瘤小鼠的生存期。因此，我们的研究结果表明，HS-TEX衍生的外泌体是一种有效的肿瘤疫苗，可以化学吸引和激活DC和T细胞，诱导更有效的抗肿瘤免疫反应。通过脂筏依赖途径通过外泌体释放趋化因子可能是趋化因子胞吐的一种新方法。
Exosomes derived from dendritic cells or tumor cells are a population of nanometer-sized membrane vesicles that can induce specific antitumor immunity. During investigation of the effects of hyperthermia on antitumor immune response, we found that exosomes derived from heat-stressed tumor cells (HS-TEX) could chemoattract and activate dendritic cells (DC) and T cells more potently than that by conventional tumor-derived exosomes. We show that HS-TEX contain chemokines, such as CCL2, CCL3, CCL4, CCL5, and CCL20, and the chemokine-containing HS-TEX are functionally competent in chemoattracting CD11c+ DC and CD4+/CD8+ T cells both in vitro and in vivo. Moreover, the production of chemokine-containing HS-TEX could be inhibited by ATP inhibitor, calcium chelator, and cholesterol scavenger, indicating that the mobilization of chemokines into exosomes was ATP- and calcium-dependent and via a lipid raft-dependent pathway. We consistently found that the intracellular chemokines could be enriched in lipid rafts after heat stress. Accordingly, intratumoral injection of HS-TEX could induce specific antitumor immune response more efficiently than that by tumor-derived exosomes, thus inhibiting tumor growth and prolonging survival of tumor-bearing mice more significantly. Therefore, our results demonstrate that exosomes derived from HS-TEX represent a kind of efficient tumor vaccine and can chemoattract and activate DC and T cells, inducing more potent antitumor immune response. Release of chemokines through exosomes via lipid raft-dependent pathway may be a new method of chemokine exocytosis.